Organic amine derivatives and method of obtaining same



. being more, soluble in Patented May 1, 1945 ORGANIC AMINE nsarva'rrvas AND METHOD OF OBTAINING SAME Edward W. Tillltson, minor to Parke,

Grosse Pointe Farms, Mich., Davis & Company, Detroit,

Mich., a corporation of Michigan No Drawing. Application June 22, 1942,

Serial No. 448.001

8 Claims. (Cl. 26021l) The invention relates to, new water soluble derivatives of sulfanilamide and N -substituted derivatives of sulfanilamide.

This application is a continuation-impart of my application, Serial No. 223,763, filed August 8, 1938, now Patent No. 2,287,071, issued June 23, 1942.

I have found that sulfanilamide and certain of its N -substituted derivatives are capable of reacting with a water soluble bisulflte salt and certain alpha hydroxy aldehydes to give new and useful products. The new products have, in greater or less degree, the valuable property of aqueous solutions than the original amine free base used in the reaction. Furthermore, the new solubilized sulfanilamide derivatives are non-toxic and not only retain the chemotherapeutic effectiveness of the original sulfanilamide compound but even surpass it in some instances.

The type formula which may be used for representing the products of the invention is,

where X is a member of the group hydrogen, sodium, ammonium, ammonium substituted by at least one allgvl, hydroxyalkyl, amino alkyl or alkylamino alkyl radical, R1 is a member of the group hydrogen, alkyl, alkyl substituted by at least one of CONH: and COOX, aliphatic acyl, aliphatic acyl substituted by at least one of CONHg and COOX, phenyl, aminophenyl, sulfonamido phenyl, sulfonalkyD amido phenyl, a heterocyclic radical having a ring of 5 to 6 atoms of the class carbon, nitrogen and sulfur. at least one of said atoms being a carbon atom and at least one being nitrogen, the heterocyclic radical being attached to the sulfonamide .nitrogen atom of the above formula through said carbon atom, and a benzoheterocyclic radical,

where P-Q is a chain of 3 to 4 atoms of the class carbon, nitrogen and sulfur, at least one of said atoms being carbon and at least one being nitrogen, the benzoheterocyclic radical being attached to the sulfonamide nitrogen atom of the general formula through said carbon atom of P-Q-, R2 is a member of the group X, alkyl, alkyl substituted by at least one of CONH: and COOX, and R3 is a member of the group hydrogen, alkyl, hydroxy alkyl and hydroxy alkyl substituted by at least one of hydroxyl, amino, CONHz, ---COOX and a lactone grouping corresponding to COOH and contained within or derived directly from the radical CHOH-Ra itself.

In the above description of the formula for the compounds of the invention, wherever the word alkyP' is used it includes only those alkyl derivatives wherein the longest unbroken chain of carbon atoms present does not exceed six.

Apparently thealpha hydroxy aldehyde bisul-- fite sulfanilamide derivatives of the invention are comparatively easily broken up in the body following administration to give products equivalent to or even superior in therapeutic action to the original sulfanilamide or its N -substituted derivative and can therefore be used instead of sulfanilamide and its N -derivatives. In many instances the aldehyde bisulflte derivatives also can be used where the unreacted sulfanilamide compound is unsuitable. The new compounds are especially valuable because of their increased solubility. r

Among the new compounds I have found a preferred group of the formula,

X SOiX where R3 and X have the same significance as in the general formula but where R4 is limited to the heterocyclic and benzoheterocyclic radicals described for R1 of the general formula.

These latter compounds are preferred because many of them are very effective antiseptics and germicides. They can be prepared for therapeutic administration in much higher concentrations than is possible with the corresponding amine free base. For example, sulfapyridine of the formula. C5H5NNH-SO2CBH4NH2. when condensed with sodium bisulfite and an aldose or sugar, such as dextrose, gives a product of many vtimes greater solubility in aqueous solution, of

the order of about 40 or more times, than that of sulfapyridine itself.

The preferred alpha hydroxy aldehydes for use in-the invention are the naturally occurring aide-sugars. These maybe any of the soluble aldo-sugars, such as mono-saccharoses or disaccharoses, and may be in the form containing free aldehyde groups or the equivalent pyranose or furanose structures.

The compounds of the preferred aldo-sugar bisulfite type are particularly useful because the sugar and the bisulflte parts of the molecule are nontoxic and readily eliminated by the body and this enhances their therapeutic value.

Examples of the aldo-sugars are the aldo pentoses such as arabinose, ribose, xylose and rhamnose, the aldo hexoses such as glucose, galactose and mannos'e, the aldoheptoses and aldo octoses, aldo disaccharides such as lactose and maltose, aldo trisaccharides and the like.

excess of the aldehyde and bisulfite As already indicated above under the general formula for the new products, the invention in its broader aspects includes reaction of the sulfanilamide compound with bisulfite and alpha hydroxy aldehydes other than the naturally occurring aldo sugars. For example alpha hydroxy aldehydes may be used which will give final products wherein R3 of the general formula is any of the follow- COONB CHOHCHOHCHOHCOOH (or its laotone) CHOH-OHOHCHOHOOONa CH OH-CHOH-CHOH-CONHs -CHOH-CH OH-CHOH-CH:

CH: -onon-o HN nion on CH OH-CHOH-CHOH-CHK OiHl -onon-onon-cnon-omn onon-on ooon -on,on

-onon-on coon -on,-ooon The sulfur in the condensation products is probably present as in a sulionic acid group,

the amine free base, the hydroxy aldehyde, andthe bisulfite salt or sulfur dioxide may be brought together in any order. Preferably, however, the bisulfite and the hydroxy aldehyde are first reacted and this reaction product is then further reacted or condensed with the amine free base or sulfanilamide compound.

In reacting the sulfanilamide or its N derivative with the hydroxy aldehyde and the bisulfite salt it may be desirable in some cases to use an since I have found that the presence of an excess of the latter two substances frequently results in concentrated, aqueous solutions of the condensate being more stable than when equimolecular proportions are reacted. For instance, a mole of sulfanilamide can be reacted with about 1.2 moles of sodium bisfulfite and about 1.4 moles of dextrose or even higher proportions to give a product which is more stable, especially in aqueous solutions of high concentration, than the product obtained by using exact equimolecular quantities of resgents.

I do not wish to limit the invention by any theory as to the reactions which occur durins formation of the new products. However, it appears that the condensation takes place somewhat as follows:

nroaon-cnonsonr+niN- orr B: Call On the basis of these reactions, there would be a possibility of decomposition of the final condensate in aqueous solutions and the presence of an excess of bisulfite salt or hydroxy aldehyde, or both, would in some cases tend to prevent the amine aldehyde bisulfite condensate from decomposing with precipitation of the less soluble amine free base.

The condensation can be carried out not only in aqueous solution but also, when the amine is suiilciently thermostable, by fusing the reactants together in'the dry state. The fact that the condensates generally have far greater solubility than the amine free bases from which they are derived, shows that, definite compounds are formed, probably in accordance with the equations given above.

When obtaining the products of the invention by fusion of the reagents in the dry state, it is preferred that the hydroxy aldehyde be brought to the liquid state, by heating if necessary, and the alkali bisulflte first added and then the amine free base. Vigorous stirring may be required and in the case of some aldehydes, such as sugars, careful temperature control may also be advisable in order to obtain a pure white product.

Obvious variations of the methods used in obtaining my products will occur to those skilled in this art. For example, a salt of the sulfanilamide compound, such as the amine hydrochloride salt or the N -sodium salt can be reacted in the presence of an alkaline sulfite or sulfur dioxide respectively to generate a bisulfite. Alternatively, one can use an aldehyde or else a sulfanilamide substituted by CO0I-I along with an alkaline sulfite in proportions to also give a bisulflte. Variations of this type can be illustrated, for example, by the following combinations of reactants.

(1) V a. mcnon-cno Nmso. nc1.Nn.- -so N/ 1 nooc-(cnomrcno NEIHOI NH BOIN/ O ng-onon-cno so, mo NH som O Na (4) omoooNa Since it has become common usage in' the literature to refer to various derivatives of sul- 9,874,701 faniiylamide by somewhat abbreviated names, the

same practice will be followed in describing sulfanilylamide derivatives employed in the examples. The following list will indicate the accepted abbreviations: r

Chemiul name Accepted abbreviation Example 1-Sultanilamide dextrose sodium sullonate (reaction in solution) 375 grams of dextrose and 145 grams of sodium bisulfite are heated to boiling in 500 cc. of water. 198 grams of sulfaniiamide are added and the boiling continued in the open air until the volum is reduced to 690 cc. This gives a clear, viscous and almost colorless. solution containing the equivalent of 0.33 gram of sulfanilamide per cc. This solution may be diluted to any desired con! centration without formation of a precipitate. It can be evaporated down to dryness to give a dry solid which is also readily soluble in water. Approximately 30 or 40 times as much of the dry product can be brought into solution as is possible with sulfanilamide itself. Furthermore, the sulianilamide dextrose sodium sulfonate product of this example has the same order of antiseptic power as an equivalent amount of sulfanilamide itself.

Example 2-Sulfanilamide sulfonate (reaction by fusion) dextrose sodium be pulverized if desired. The reaction product is the same as that obtained in Example 1 andvhas the same properties.

Example 3-Sul/anilamide d-aalactose sodium sulfonate 24.3 grams of d-galactose and 12.5 grams of sodium bisulnte are dissolved in about 50 cc. of hot water. About 17.2 grams of sulfanilamide are added and the heating continued for about 30 minutes. The reaction product may be diluted further with water or may be brought to dryness as described for the product of Example 1 above.

Example 4-Suljanilamide maltose sodium sulfonate 27 grams of maltose and 6.2 grams of sodium bisuli'ite are heated in about 50 cc. of water. 8.6 grams of suli'anilamide are thenadded and the heating continued until solution is complete. The solution of the sulfanilamide maltose sodium sulfonate thus obtained is rather concentrated and it may be either brought to dryness. to give the solid product or may be diluted further with water or other solvent.

' trample 5-Sul/anilamide lactose sodium sullonate 36 grams of lactose, 10.5 grams of sodium bisuliite and 17 grams of sulfanilamide' are added to about 300 cc. of water and heated until the reaction is complete and all of the product is in Example 6-Sul/anilamide alwoeraldehvde sodium suljonate 93 grams of um bisuiflte and 170 grams heated in 250 cc. of water until solution is complete. The resulting solution of the reaction product can be obtained in dry form by evaporation of the solvent.

Eeample 7-p'-Aminobenzene sul/onul p-amino benzene sulfonamidedea'trose sodium sul/onate of sulfanilamide are ilte are boiled in 20 cc. of water until solution is' which readily dissolves in greater than is possible with used as a starting material.

Example 8-Sul/apyridine-M-deztrose sodium sulfonate (reaction in solution) concentrations far the amine free base without reflux for about an hour or until the solution becomes clear. Water and alcohol are added from time to time to make up for solvent lost by evaporation if a condenser is not used. The clear solution is boiled until the temperature rises to -103 to remove all alcohol. The volume is then adjusted to 200 cc. with water to give a stable solution containing the equivalent 250 mg./cc of sulfapyridine. The solution has a pH of approximately 6 and is suitable for injection as such or it may be diluted.

If a solid product is desired the above solution may be evaporated to dryness under reduced pressure and the solid pulverized. The powder readily redissolves on mixing and/or warming with a little water.

Example Q- -SuUapyridine-N -de:z:trose sodium sul/onate (reaction by fusion) discolored somewhat.

Example I0Sulfapyridine-N-galactose sodium sulfonate 5 g. of sulfapyridine, 10 g. 01' d galactose. and 2 g. ('1' sodium bisulflte are boiled with 15 cc. of water and 10 cc. of alcohol. The boiling is continued until the solution becomes clear. Water llyccraldehyde. 104 grams of sodi-' mass. After grinding 4 w e and alcohol are added from time to time to replace part of that which is evaporated. The clear 2.5 g. of sulfapyridine, 5 g. sodium bisulflte, 8 cc. of water, and 5 cc. are heated together as in Example 8.

Example 12-Sulfapyridine-M-arabinose sodium sulfonate 5 g. of sulfapyridine, 9 g. oi'arabinose, 2 g. sodium bisulfite, 15 cc. of water, and 10 cc. of alcohol are boiled on an electric hot plate until the solution becomes clear. Water and alcohol in small quantities are added replace that lost by evaporation. The clear solution is heated to approximately 100 to remove thealcohol and is then made up to a volume of 25 cc. with water and filtered giving a concentration equivalent to 200 mg./cc. of sulfapyridine. The filtered solution may be placed in ampoules and then sterilized by heating at 80 for V2 hour on three successive days.

of mannose, 1 g. of alcohol Example 13-Sulfapyridifie-N4actose or maltose sodium sullonate 5 g. of sulfapyridine, 20 g. of lactose or maltose, 2 g. of sodium bisulflte, 15 cc. of water, and 10 cc. of alcohol were boiled until the solution cleared.

Water and alcohol were added from time to time 35 to make up for part of that lost by evaporation.

from time to time to The clear solution was heated to 100-105" C. to

remove the alcohol. The resulting solution was made up to cc. and filtered. The resulting solution contains the equivalent of apprommately 165 mg./cc. of sulfapyridine.

Example '14-Sulfamethylthiazole dextrose sodium sulfonate 1.0 g. sulfamethylthiazole, 2 g. dextrose, 0.4 g.

sodium bisulfite are heated in a few cc. of water and alcohol until the solution becomes clear. The alcohol is boiled of! giving a clear aqueous solution. Part of the solution is evaporated to dryness giving a friable porous solid which is readily powdered. The in water to give a clear solution.

Example 15-Sulfathiazole dextrose sodium suljonate 5 g. sulfathiazole, bismfite, 15 cc. water, and 15 cc. alcohol are refluxed until the solution clears. The alcohol is boiled oil and the resulting clear solution after filtering to remove specks is evaporated to dryness under reduced pressure with or without the aid of a desiccant giving a brittle porous solid the powder readily redissolves in water giving a clear stable solution which is useful therapeutically.

Example Iii-Sulfathiazole dextrose sodium sul- Ionate dry powder readily redissolves 8 g. dextrose, 2.1 g. sodium 55 1 hour or until solution is mg. /cc. of sulfathiazole. The solution is suitably stored in closed containers such as ampoules. It is useful therapeutically.

Example 17--Suljathiazole aalactose ion-ate sodium lulfonate. The solution may be evaporated to-dryness to give a solid product which will readily redissolve and is therapeuticallyuseful.

Example 18-Sullathiaeole maltose monolsopropanol ammonium sulfonate 0 stable solutions.

Example 19-Sullathiazole dextrose monoisopropanel ammonium suljonate If themaltose of Example 18 is replaced with approximately 3.56 g. dextrose, a product of similar character is! obtained.

Example 20-Sulfdthiazole xulose monoethanol ammonium sulfonate 2.5 g. 2-sulfanilylamido-thiazole,3 g. xylose,and 1.5 g. monoethanol ammonium bisulflte are mixed with 10 cc. water and brought to a boil whereupon a, clear stable solution results containing suliathiazole wlose monoethanol ammonium sulfonate. The solution and the solid obtained by evaporation are therapeutically useful.

Example 21 --,Sulfapvridine dextrose monoethanol ammonium sulfonate 2.5 g. sulfapyridine, 5.2 g. dextrose, and 1.8 g. monoethanol ammonium bisulflte are mixed with 30 cc. water and 20 cc. alcohol and boiled. The

. solution becomes clear in a few minutes. The

alcohol is removed by tion has a volume 01' about stable. A stable solid may be obtained from the solution by evaporation. Both the solid and solution are useful therapeutically.

Example 22-Sullanilamide dextrose monoethanol ammonium suljonate 1.72 g. sulianilamide, 3.2 g. dextrose, and 1.5 g. monoethanol ammonium bisulfite are mixed with 10 cc. water and warmed. The solution soon becomes clear giving a solution or sulfanilamide dextrose monoethanol ammonium sulfonate.

Example 23-Sul,fanilamtde xylose ammonium suljonate boiling. The cooled solu- 18 cc. It is clear and liquid, or sublimation oi the solvent from the irozen state. Both the solution and the solid are therapeutically useful.

Example 24-Sul/anilamide dextrose Wm panol ammonium suljonatc 1.72 g. sulianilamide, 3 g. dextrose, and 8.4 g.

triisopropanol ammonium bisulnte are mixed with cc. water and heated. The sulianllamide soon reacts and is carried into solution. The solubility or the sulianilamide compound is so great that the solution may be concentrated to a thick syrup without evidence of precipitation.

Example -Suljadiazine dextrose triisopropanol ammonium sulfonate 2.5 g. suliadiazine, 5.2 g. dextrose and 4.1 g. trlisopropanol ammonium bisuliite are mixed with 20 cc. water and cc. alcohol. The mixture is boiled giving a clear solution of suliadiazine dextrose triisopropanol ammonium sulionate which may be obtained in solid form by removing the remaining solvents.

Example 26-Sulfadiazine dextrose sodium suljonate 12.5 g. sulfadiazlne, g. dextrose, and 7 g. sodium bisulfite' are heated in about 100 cc. water and 100 cc. alcohol and boiled until the solution clears. Water and alcohol may be added from timetotimetomakeupior thatlostdueto evaporation. The clear solution isheated to 100-105 to remove all alcohol. The volume may be adjusted to 100-150 cc. depending on the concentration desired. The product is a therapeuti cally useful combination. It may be isolated in solid form by removal of the remaining solvent.

Example 27-Sulfadiazine maltose sodium sulfonate 16 g. sulfadiazine. 72 g. maltose. and 12 3. sodium bisulflte are boiled in 225 cc. water and 100 cc. alcohol. Water and alcohol are added from time to time to make up for that lost by evaporation. After the solution becomes clear the alcohol is boiled out by raising the temperature to 100-106. The resulting solution may be used therapeutically. The product 01' this example,

has the 1011111118.,

on c? \N t -NH-SDrO-NH-CH-CuHuOm N AOlNB Example 28-Sulfaouanidine dextrose sodium sullonate 21.4 g. sulfaguanidine, g. dextrose, and 10.6 g. sodium bisulfite are brought to a boil in 100 cc. water. The sulfaauanidine soon reacts with the dextrose sodium sulionate giving a clear solution which may be used therapeutically.

Example 2.9-Sul/ddliaci1ie dextrose ammonium sullonate 2.5 g. suliadiazine, 8 g. dextrose, 2 g. ammonium bisulfite (added as a solution) are heated with 15-20 cc. water and 10-20- co. alcohol until the sulfadiazine reacts and goes into solution. The alcohol is boiled 01! giving a stable aqueous solution. It is useiul therapeutically. A solid which readily redissolves may be obtained by evaporating to dryness under reduced pressure. Both the solid and liquid are therapeutically useful.

Example JFSul/aauanidtne lactose ammonium suljonate 1 2.14 s. suliguanidine. 12 I. lactose, 1.5 g. ammonium bisulrite (as 50% solution) are heated in 20 cc. water. The mixture readily reacts to form a clear solution which may be used therapeuticslly- Example 31Sultan.lamide alyceraldehpde sodium sultonate 1.72 g. sulianilamide. 1.5 g. glyceraldehyde. and 1.04 g. sodium bisuliite are heated in 10 cc. water until the solution clears. The solution oi sulianilamide glyceraldehyde soduim suli'onate thus iorme is useful therapeutically.

Example .lz-suljathiazole sodium gluc'uronate sodium sullonate 2.5 g. suliathiazole, 2.5 g. glucuronic acid, and 1.3 g. sodium suli'ite are heated in 10-15 co. water and 10-15 cc. alcohol until the suliathiazole reacts and goes into solution. The alcohol is removed by boiling. The resulting aqueous solution of suliathiazole sodium glucuronate sodium sulionate is stable and therapeutically useiul.

Example 33-Sulfathiazole sodium aalacturonate sodium sulfonate Substitution of 2.5 g. galacturonic acid tor the gulcuronic acid oi Example'32 produces a product oi the same character.

Example 3i-M-di-(p-hydroxy ethyl) sul/anilamide dextrose sodium sulfonate 2.6 g. N -di-(p-hydroxy ethyl) sulianilamide, 3.1 g. dextrose, 1.2 g. sodium bisulflte are heated in 15 cc. water and 3 cc. propylene glycol until the N -sultanilamide derivative reacts and dissolves giving an aqueous propylene glycol solution oi N -di-(p-hydroxy etlwl) sulianilamide.

Example 35-M-di-(p-hfldroxp ethyl) suljanilamide rtbose trimethplol methyl ammonium sul/onate Example 36-51 qmethpl-N -suljanilul suljanil-- amide maltose amino-ethylene ammonium sullonate 3.4 g. N -methyl-N*-suli'anilyl sulfanilamide. 7.5 g. maltose, and 2 g, ethylene diamine monobisuliite are heated in 15-20 cc. water and 5 cc. glycerol until the sulfanilamide derivative reacts to give a clear solution. This solution is useful therapeutically.

Example 37N -dimethyZ-N-suljanilpl sulfdnilamide lactose piperazine sulfonate 3.5 g. N -dimethyl-N -sulfanilyl sulianilamide. 7.2 g. lactose. and 2 g. piperazine mono-bisulflte are heated with 15-20 cc. water and 5 cc. propylone glycol. The sulianilamide derivative soon reacts to give a clear solution. The solution may be used therapeutically. I

sodium suljonate 2.1 g. N -acetyl sulfanilamide, 3 g. galactose, and 1.1 g. sodlum'bisulfite are reacted as in Example 21. 1

Example 39-N -sodium carbon! methylene sulfanilamide sodium aalacturonate sodium sulfonate 2.5 g. lq -sodium carboxymethylene sulfanilamide, 2.0 g. galacturonic acid, 1.3 g. sodium sulfite, are mixed in 15-20 cc. water and warmed. Complete solution soon results due to the rapidity of the reaction. The solid product which readily redissolves to give clear solutions may be isolated by dehydrating the solution. Both the solution and the solid may be used therapeutically.

Example 40-2-suljanilylamido benzothiazole ammonium alucuronate ammonium sulfonate 3 g. sulianilylamido benzothiazole, and 2.5 g. glucuronic acid are warmed in sumcient 85% alcohol to form a solution. 0.72 g. sulfur-dioxide is added. 0.41 g. ammonia dissolved in about 15 cc. water is added. The alcohol is boiled oil giving a solution which may be used therapeutically.

Example 41-2-suljanilulamido thiazolo'ne yalac turonamide ethyl ammonium sulfonate 2.7 g. z-sulfanilylamido thiazolone, 2.6 g. galacturonamide, 1.31 g. ethyl ammonium bisulflte are warmed in 15 cc. alcohol and 15 cc. water until the 2-sulfanilylamido thiazolone dissolves. The alcohol is removed by evaporation giving a clear solution which may be used therapeutically. 7

Example 42-2-sulfanilylamido indazole rhamnose t-diethyl amino-(a-methyl) butyl ammonium sulfonate N-SOr-ONE-CH-CHOH-R v R: 403x where x is a member of the group consisting of hydrogen, sodium, ammonium, ammonium substituted by at least one alkyl, hydroxyallwl; amino alkyl and alkylamino alkyl radical, R1 is a member of the groupconsisting of hydrogen, alkyl, alkyl substituted by at least one of --CONH: and COOX, aliphatic acyl, aliphatic acyl substituted by at least one of CONI-Ia and --COX, phenyl, aminophenyl, sulfonamido phenyl, sulfon- (alkyl) -amido phenyl, a heterocyclic radical having a ring of 5 to 6 atoms of the class consisting of carbon, nitrogen and sulfur, at least one of said atoms being a carbon atom and at least one being nitrogen, the heterocyclic radical being attached to the sulfonamide nitrogen atom of the above 2,374,791 Example 38-N -acetyl suljanilamide aalactose formula through said carbon atom, and a' benzo heterocyclic radical,

P on

I v Ct where -PQ is a chain of 3 to 4 atoms of the class consisting of carbon, nitrogen and sulfur, at least one of said atoms being carbon and at least one being nitrogen, the benzoheterocyclic radical being attached to the sulfonamide nitrogen atom of the general formula through said carbon atom of -PQ, R2 is a member of the group consisting of X, alkyl, aikyl substituted by at least one of --CONH2 and -CO0X, and R: is a member of the group consisting of hydrogen, alkyl, hydroxy alkyl and hydroxy alkyl substituted by at least one of hydroxyl, amino, -CONH2, --COOX and a lactone grouping corresponding to -COOH and contained within or derived directly from the radical -CHOHRs itself, the term alkyl including only those alkyl derivatives wherein the ionsest unbroken chain of carbon atoms present does not exceed 6.

2. A compound of the formula.

OH-N

\ /C-NH-SOrONE-(iH-(CHOHMCH: on

\ o-Nn-sm-Oun-xgnqononnomon H-S OINa 4. A dextrose derivative of the formula,

0|Ne 5. A. maltose derivative of the formula ON H-O H110 1o 6. Method for obtaining a derivative of para amino benzene sulfonamide which comprises bringing together at a reacting temperature not 0 substantially above about 155 C. abisulfite of formula xnsm, and alpha hydroxy aldehyde of formula formula,

Ba-QHOH-CHO and a para amino benzene sulfonamide oi formule,

CO0X, aliphatic acyl, aliphatic acyl substituted by at least one of CON H2 and -CO0X, phenyl, aminophenyl, sulfonamido phenyl, sulfon-(alkyl) -amino phenyl, a heterocyclic radical having a ring of 5 to 6 atoms of the class consisting of carbon, nitrogen and sulfur, at least one of said atoms being a carbon atom and at least one being nitrogen, the heterocyclic radical being attached t the sulfonamide nitrogen atom of the above formula through said carbon atom, and a benzoheterocyclic radical,

where PQ class consisting at least one of said atoms being carbon and at least one being nitrogen, the benzoheterocyclic radical being attached to the sulfonamide nitrogen atom of the general formula through said carbon atom of PQ, R2 is a member of the group consisting of X, allwl, alkyl substituted by at least one of -CONH: and COOX, and R3 is a member of the group alkyl, hydroxy alkyl and hydroxy alkyl substituted by at least one of hydroxyl, amino, COHN2, COOX and a lactone grouping corresponding to -COOH and contained'within or derived directly from the radical CHOHRa itself, the term alkyl including only those alkyl derivatives wherein the longest unbroken chain of carbon atoms present does not exceed 6.

EDWARD W. TILLITSON.

consisting of hydrogen. 

